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What causes Opitz G/BBB syndrome?

The X-linked form of Opitz G/BBB syndrome is caused by mutations in the MID1 gene. The MID1 gene provides instructions for making a specific protein called midin. This protein helps regulate the function of microtubules, which are rigid, hollow fibers that make up the cell's structural framework (the cytoskeleton). Microtubules help cells maintain their shape, assist in the process of cell division, and are essential for the transport of materials within cells. The MID1 gene is a member of a group of genes called the TRIM (tripartite motif) family. The proteins produced from this large family of genes are involved in many cellular activities. Primarily, TRIM proteins play a role in the cell machinery that breaks down (degrades) unwanted proteins. As part of its protein degrading function, midin is responsible for the breakdown of an enzyme called protein phosphatase 2A (PP2A). This enzyme regulates a number of microtubule-associated proteins, as well as other proteins involved in critical cellular processes such as cell division. When a mutation causes the midin protein to malfunction, PP2A accumulates in the cell and alters the function of the microtubule-associated proteins. These changes disrupt microtubule function, and cells can have difficulty dividing properly. The nonfunctional midin protein binds with itself (aggregates) and forms protein clumps in the cells. However, it is currently unclear how these changes disrupt normal development and cause the birth defects associated with Opitz G/BBB syndrome. Some people who have a family history of X-linked Opitz G/BBB syndrome have no detectable MID1 mutation. The reason for this is not yet known, although some researchers have suggested the involvement of other unknown genes.[1]

The autosomal dominant form of Opitz G/BBB syndrome is caused by a deletion of a small piece of chromosome 22, specifically 22q11.2, which is why researchers consider this condition to be part of 22q11.2 deletion syndrome. It is not yet known which deleted gene(s) within this region of chromosome 22 specifically cause the signs and symptoms of Opitz G/BBB syndrome.[1]